Thyroid hormone receptors (TRs) are essential for growth, differentiation, and development. There are two TR genes, alpha and beta, which yield four thyroid hormone (T3) binding isoforms-TRalpha1, TRbeta1, TRbeta2, and TRbeta3. Given the critical roles of TRs in cellular functions, it is reasonable to expect that mutations of TRs could have deleterious effects. Indeed, mutations of the TRbeta gene are known to cause a human genetic disease, thyroid hormone resistance syndrome (RTH). For the past several years, we have been using the powerful tool of mouse genetics to understand the molecular mechanisms of thyroid hormone action in vivo. We have also created knockin mice harboring a TRbeta (TRbetaPV) or TRalpha1 (TRalpha1PV) mutation to delineate the molecular basis of diseases due to mutations of TRs, thus providing a platform for translation of basic research to disease prevention, diagnosis, and treatment. Significant advances are highlighted below. Steroid hormone receptor coactivator-3 contributes to the pathogenesis of resistance to thyroid hormone.Resistance to thyroid hormone (RTH) is a disease caused by mutations of the TRbeta gene. A mutation (TRbetaPV) derived from an RTH patient (PV) at NIH was targeted to the TRbeta gene locus by using homologous recombination and the Cre/lox system (TRbetaPV mouse). TRbetaPV mice faithfully reproduce the human RTH. Through use of this mouse model, it has become possible, for the first time, to address several critical, clinically relevant issues. We have shown that RTH symptoms are caused by the interference of TRbeta mutants with the transcriptional activity of wild-type TRalpha1 and TRbeta in vivo. We have also discovered that variable phenotypic manifestation of RTH patients is dictated by tissue-dependent abundance of TRbeta and TRalpha1 isoforms, the promoter context of T3 target genes, and the contribution of a novel "change-of-function" of TRbeta mutants. We previously identified the steroid hormone receptor coactivator-1 (SRC-1) as one of the factors that modulate the target-tissue responsiveness in RTH. SRC-1 belongs to the p160 family of coactivators that includes SRC-2 and SRC-3. Despite sequence similarity in the functional domains of these SRC coactivators, the phenotypes exhibited by mice deficient in SRC-1 and SRC-3 are distinct, suggesting that these two activators have preferential roles in different tissues in vivo. These observations prompted us to ascertain whether SRC-3 has different regulatory roles in the molecular actions of TRbeta mutants in vivo, thereby contributing to the variable phenotypic manifestation of RTH. Indeed, we found that the lack of SRC-3 reduces the growth of both the pituitary and thyroid in TRbetaPV mice, and thus lessens the dysregulation of the pituitary-thyroid axis. In contrast, the lack of SRC-3 exacerbates the growth impairment observed in TRbetaPV mice. Further studies indicated that this modulatory effect of SRC-3 on growth is mediated via the insulin growth factor-1 (IGF-1)/PI3K/AKT/mTOR signaling pathway. Therefore, SRC-3 modulates the manifestation of RTH via TR-dependent and TR-independent pathways. The present study provides new insight into the pathogenesis underlying RTH. Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta.Thyroid hormone regulates bone turnover and mineralization in adults and is essential for skeletal development. Using TRbetaPV mice, we previously identified a phenotype of skeletal thyrotoxicosis due to mutation of the TRbeta gene. In order to characterize mechanisms underlying T3 action in bone, we analyzed skeletal development in TRalpha1PV mice in which the same PV mutation was targeted to TRalpha1.